The present invention relates to the delivery of stimulants through an inhalation route. Specifically, it relates to aerosols containing ephedrine or fenfluramine that are used in inhalation therapy.
There are a number of compositions currently marketed as stimulants. The compositions contain at least one active ingredient that provides for observed therapeutic effects. Among the active ingredients given in stimulant compositions are ephedrine and fenfluramine.
It is desirable to provide a new route of administration for ephedrine and fenfluramine that rapidly produces peak plasma concentrations of the compounds. The provision of such a route is an object of the present invention.
The present invention relates to the delivery of stimulants through an inhalation route. Specifically, it relates to aerosols containing ephedrine or fenfluramine that are used in inhalation therapy.
In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of ephedrine or fenfluramine. Preferably, the particles comprise at least 10 percent by weight of ephedrine or fenfluramine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of ephedrine or fenfluramine.
Typically, the aerosol has a mass of at least 10 xcexcg. Preferably, the aerosol has a mass of at least 100 xcexcg. More preferably, the aerosol has a mass of at least 200 xcexcg.
Typically, the particles comprise less than 10 percent by weight of ephedrine or fenfluramine degradation products. Preferably, the particles comprise less than 5 percent by weight of ephedrine or fenfluramine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of ephedrine or fenfluramine degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is in amorphous form.
Typically, where the aerosol comprises ephedrine, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 15 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 12.5 mg/L.
Typically, where the aerosol comprises fenfluramine, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 30 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 25 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 22.5 mg/L.
Typically, the aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL or 108 particles/mL.
Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.1.
Typically, the aerosol is formed by heating a composition containing ephedrine or fenfluramine to form a vapor and subsequently allowing the vapor to condense into an aerosol.
In a method aspect of the present invention, either ephedrine or fenfluramine is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of ephedrine or fenfluramine, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition that is heated comprises at least 10 percent by weight of ephedrine or fenfluramine. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of ephedrine or fenfluramine.
Typically, the particles comprise at least 5 percent by weight of ephedrine or fenfluramine. Preferably, the particles comprise at least 10 percent by weight of ephedrine or fenfluramine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of ephedrine or fenfluramine.
Typically, the aerosol has a mass of at least 10 xcexcg. Preferably, the aerosol has a mass of at least 100 xcexcg. More preferably, the aerosol has a mass of at least 200 xcexcg.
Typically, the particles comprise less than 10 percent by weight of ephedrine or fenfluramine degradation products. Preferably, the particles comprise less than 5 percent by weight of ephedrine or fenfluramine degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of ephedrine or fenfluramine degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.1.
Typically, where the aerosol comprises ephedrine, the delivered aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 15 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 12.5 mg/L.
Typically, where the aerosol comprises fenfluramine, the delivered aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 30 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 25 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 4 mg/L and 22.5 mg/L.
Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL or 108 particles/mL.
Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108 particles per second. Preferably, the aerosol is formed at a rate greater than 109 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010 inhalable particles per second.
Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.
Typically, where the condensation aerosol comprises ephedrine, between 2 mg and 20 mg of ephedrine are delivered to the mammal in a single inspiration. Preferably, between 2 mg and 15 mg of ephedrine are delivered to the mammal in a single inspiration. More preferably, between 2 mg and 12.5 mg of ephedrine are delivered in a single inspiration.
Typically, where the condensation aerosol comprises fenfluramine, between 4 mg and 30 mg of fenfluramine are delivered to the mammal in a single inspiration. Preferably, between 4 mg and 25 mg of fenfluramine are delivered to the mammal in a single inspiration. More preferably, between 4 mg and 22.5 mg of fenfluramine are delivered to the mammal in a single inspiration.
Typically, the delivered condensation aerosol results in a peak plasma concentration of ephedrine or fenfluramine in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02 or 0.01 h.
In a kit aspect of the present invention, a kit for delivering ephedrine or fenfluramine through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of ephedrine or fenfluramine; and, b) a device that forms an ephedrine or fenfluramine aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of ephedrine or fenfluramine.
Typically, the device contained in the kit comprises: a) an element for heating the ephedrine or fenfluramine composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.